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Unit of Pediatric Neurology, Pediatric Department, Hospital Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, PortugalNeurology Department, Hospital Prof. Dr. Fernando Fonseca, Amadora, Lisbon, Portugal
Linear scleroderma en coup de sabre presents with sclerotic lesions of the skin.
Subcortical white matter lesions are ipsilateral to craniofacial scleroderma.
Hemiplegic migraine induced by exercise is a rare neurological manifestation.
Some patients require aggressive immunosuppression.
There is evidence of central nervous system inflammation and vasculitis.
We report the case of a 9-year-old girl with linear scleroderma en coup de sabre (LSCS) who developed progressive white matter involvement, presenting as intractable hemiplegic migraine-like attacks induced by exercise. After a period of severely aggressive course, clinical and radiological stabilization was achieved under immunosuppressant treatment. Intrathecal synthesis of IgG and lymphocytic pleocytosis provided indirect evidence of a chronic inflammatory process of the central nervous system. We discuss the possible immunopathogenic mechanisms responsible for the neurocutaneous involvement in LSCS, favouring the hypothesis of an autoimmune and inflammatory vasculopathy. The singular occurrence of hemiplegic migraine triggered by exertion add further insight to the currently unknown pathogenesis of scleroderma disorder. In addition, we highlight the importance of intensive immunosuppression approaches in selected cases, contrasting with the classic benign course of LCSC.
Localized scleroderma represents a rare group of disorders of unknown etiology characterized by sclerotic lesions of the skin and underlying tissues, being distinguished from systemic scleroderma by the absence of internal organ involvement. Linear scleroderma en coup de sabre (LSCS) is a form of localized scleroderma associated with band-like fibrotic lesions involving the frontoparietal area (
). Central nervous system (CNS) involvement has been increasingly recognized in these disorders, denoting a vast spectrum of neurological manifestations, such as seizures, focal deficits, headache and neuropsychiatric disturbances (
). Brain involvement ipsilateral to the scleroderma is a striking pattern and almost always respects the midline. The most common neuroimaging findings are parenchymal calcifications, cortical atrophy, blurring of the grey-white matter junction and T2-hyperintense white matter lesions with variable degrees of contrast-enhancement (
Evidence on hemiplegic migraine mimickers as part of the neurological LSCS spectrum is very scant. We report a case of rapidly progressive LSCS presenting with severe hemiplegic migraine attacks triggered by exertion, adding new insight to the currently unknown pathophysiology of such disorder.
2. Case presentation
A previously healthy 9-year-old girl presented a progressive cranial deformation over the left parasagittal frontoparietal area. Physical examination revealed a 6 × 14 cm band-like hyperpigmented skin lesion with associated alopecia (Fig. 1A). There was no facial atrophy. Clinical and imagiological assessment ruled out other organ involvement. The patient was born at full-term, after uncomplicated pregnancy and delivery, and had no relevant past medical history. There was no family history of autoimmune, rheumatological or scleroderma disease. The diagnosis of linear scleroderma en coup de sabre was concluded based on clinical grounds. Brain CT disclosed a frontoparietal skull deformity with furrow of the skin and outer diploe atrophy (Fig. 1B). No parenchymal abnormalities were present at that time and CT angiogram was equally normal. Laboratory investigation revealed a 1:320 titer of antinuclear antibodies (ANA) with nucleolar pattern. The remaining autoimmune screening was negative, including anti-double-stranded DNA, anticentromere, anti-Scl70 and anti-RNP antibodies. Baseline hematology and sedimentation velocity were normal. Treatment with topical corticosteroids was maintained for three months with effective skin lesion control. The patient remained clinically stable during the following four years, when at 13 years of age she developed right hemibody tonic seizures with secondary generalization, which easily remitted with levetiracetam 1000 mg daily. Subsequent electroencephalograms (EEG) revealed left hemispheric slowing and minimal epileptiform activity. Initial brain MRI disclosed two subcortical T2-hyperintense lesions involving the parieto-occipital region ipsilateral to the scleroderma, with no contrast enhancement (Fig. 2A). Intracranial MRI angiography remained unremarkable.
Two years later, she experienced recurrent episodes of altered speech and right hemiparesis, starting in the hand and progressing to face and inferior limb. A bifrontal pulsatile headache associated with nausea and vomiting would gradually install after ten minutes. During the events, neurological examination was remarkable for global aphasia, right hemihypesthesia and hemiparesis (MRC 3/5). Both headache and neurological deficits would reach maximum severity in two hours and lasted one to two days. These events were always triggered by moderate to intense physical activity during the preceding hours, such as walking long distances or climbing stairs. Subsequent MRI revealed a widespread progression of the white matter lesions associated with numerous microbleeds (Fig. 2B-D). No calcifications were present. Monitoring video-EEG recorded during the attacks were unremarkable, excluding an epileptic nature for the paroxysmal events. Cerebrospinal fluid (CSF) analysis disclosed an intrathecal synthesis of IgG with oligoclonal bands, elevated IgG index and lymphocytic pleocytosis (29 cels/mm3). Genetic testing for CACNA1A was negative. Hemiplegic migraine-like attacks induced by exercise were considered to be related with the severe progression of scleroderma brain involvement, as alternative diagnoses were properly excluded. Each attack resolved completely with administration of a 3 to 5-days course of high-dose methylprednisolone (1 g od). The patient was initially treated with methotrexate 7.5 mg weekly and oral prednisolone 60 mg daily, which was slowly discontinued thereafter. A therapeutic trial with topiramate was concomitantly started and intense physical activity was evicted.
After six months of clinical remission, unexpected deterioration occurred with an outburst of prolonged attacks refractive to oral corticosteroids, methotrexate and intravenous immunoglobulin. Each event lasted approximately seven days. Between the attacks, permanent cognitive dysfunction was evidenced, including mild intellectual disability and decline in school performance. Due to lack of efficacy of increasing methotrexate dose, it was switched to cyclophosphamide and intravenous high-dose corticosteroid regimen was reintroduced. The episodes of hemiplegic migraine remained intractable for two months, until complete resolution was achieved by intensive immunosuppression. Currently at two years of follow-up, the patient remains clinically and radiologically stable on cyclophosphamide and prednisolone 5 mg daily.
The pathogenesis of neurological involvement in localized scleroderma remains controversial, however there is crescent evidence supporting that intracranial vasculature is the primary target of an autoimmune phenomenon circumscribed to the area affected by the craniofacial scleroderma (
). Intrathecal antibody synthesis and lymphocytic pleocytosis, as observed in our patient, are highly suggestive of a chronic inflammatory process involving the CNS. In addition, few neuropathological studies have also reported inflammatory changes involving the brain parenchyma, vessels and meninges (
). This hypothesis is further supported by the observation of effective treatment response to immunosuppressant agents. In addition, other pathomechanisms have also been proposed, such as sympathetic dysregulation, vascular dysgenesis and neuronal migration defect.
Nonspecific headache is one of the dominant features of localized scleroderma (
). Contrasting with its usually benign course, our patient had a unique presentation characterized by intractable hemiplegic migraine-like attacks. This relentless progression was associated with a prominent extension of subcortical lesions and diffuse microbleeds. Both factors suggest that a microangiopathic process is responsible for a transient cerebral dysfunction during the paroxysmal events. Hemiplegic migraine mimickers are an exceptionally rare manifestation of localized scleroderma. To our knowledge, only one report of hemiplegic migraine has been previously described in literature, favouring the complex gamut of scleroderma neurological manifestations (
). In our patient, the repeated pattern of aphasic and motor aura followed by migraine indirectly supports the concept of an inflammatory vasculopathy in scleroderma.
Notably, these long-lasting attacks were always precipitated by exertion, suggesting physical exercise as a causative effect. We speculate that cerebral vasoconstriction, resulting from hypocapnia and hyperventilation, may play a significant role in triggering hemiplegic migraine bouts. In addition, other possible contributors to prolonged auras include transitory ischaemia and sympathetic dysfunction.
In conclusion, we speculate that in our patient physical exertion was the main precipitator for the transitory neurovascular dysfunction occurring in a background of a neurological inflammatory process, adding novel evidence to the currently unknown immunopathogenesis of localized scleroderma.
No funding was secured for this study.
The authors have no financial relationships relevant to this article to disclose.
Declaration of Competing Interest
The authors have no conflicts of interest to disclose.
Neuroimaging findings in scleroderma en coup de sabre.